Recent models of basal ganglia organization have dichotomized striatal projection neurons into two types: 1) neurons containing substance P (SP) that are rich in D1 type dopamine receptors and play a role in promoting desired movement; and 2) neurons that contain enkephalin (ENK) that are rich in D2 type dopamine receptors and play a role in suppressing unwanted movements. We believe that the dichotomy of striatal projection neurons into two major types may be inadequate and we believe the means by which the cortex might differentially control the different types of striatal projection neurons is unresolved. We propose studies to address these issues. First, single-cell RT-PCR in young rats indicates that at least 20 percent of striatal projection neurons co-contain SP and ENK and are functionally distinct in their dopamine and glutamate receptor characteristics. While the precise identity of the SP/ENK population is uncertain, available data suggest that the SP/ENK neurons may primarily include striatal neurons projecting to substantia nigra pars reticulata and/or pars compacta. Our first aim will use a combination of single-cell RT-PCR, double-label in situ hybridization histochemistry, and retrograde neuronal labeling to determine the phenotypic traits (dynorphin, neurotensin, calbindin and mu opiate receptor content), abundance, distribution, projections, age-related stability, and interphyletic stability of the SP/ENK population relative to the SP-only and ENK-only populations. We will also determine if the SP/ENK neurons in mice and monkeys are typically rich in both D1 and D2 receptors, as appears to be the case in rats. Secondly, we will explore the possibility that the different types of striatal projection neurons carry different signals related to movement control because they receive inputs from different cortical neuron types and/or different cortical regions. To address this issue, we will combine selective anterograde labeling of different types of corticostriatal input and retrograde or intracellular labeling of specific striatal projection neuron types to determine by dual label ultrastructural methods if striatal projection neuron types differ in the inputs they receive from either: 1) the two major types of corticostriatal projection neuron (pyramidal tract versus nonpyramidal tract); or 2) somatosensory cortex versus motor cortex. Our studies will provide insight into normal basal ganglia function and potentially into the cellular bases of diseases of basal ganglia (e.g. Huntington's and Parkinson's disease), which may in turn make it possible to devise more effective preventive and therapeutic measures for such disorders.